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Haplotypes extending across ACE are associated with Alzheimer's disease

Wilman, Bj�rn; Wilcock, Gordon K.; Kehoe, Patrick G.; Bennett, Anna M.; Katzov, Hagit; Feuk, Lars; Johansson, Boo; de Faire, Ulf; Cairns, Nigel J.; Brookes, Anthony J.; Blennow, Kaj; Prince, Jonathan A.

Authors

Bj�rn Wilman

Gordon K. Wilcock

Patrick G. Kehoe

Anna M. Bennett

Hagit Katzov

Lars Feuk

Boo Johansson

Ulf de Faire

Nigel J. Cairns

Anthony J. Brookes

Kaj Blennow

Jonathan A. Prince



Abstract

Numerous genes have been implicated in Alzheimer's disease (AD), but, with the exception of a demonstrated association with the E4 allele of APOE, findings have not been consistently replicated across populations. One of the most widely studied is the gene for angiotensin I converting enzyme (ACE). A meta-analysis of published data on a common Alu indel polymorphism in ACE was performed which indicated highly significant association of the insertion allele with AD (OR 1.30; 95% CI 1.19-1.41; P = 4 × 10 -8 ). To further explore the influence of ACE on AD, several single-nucleotide polymorphisms (SNPs) were genotyped in five independent populations represented by over 3100 individuals. Analyses based upon single markers and haplotypes revealed strong evidence of association in case - control models and also in a model examining the influence of variation in ACE upon cerebrospinal fluid levels of amyloid β42 peptide (Aβ42). The most significant evidence for association with AD was found for an SNP, A-262T, located in the ACE promoter (OR 1.64; 95% CI 1.33-1.94; P = 2 × 10 -5 ). Estimates of population attributable risk for the common allele of this SNP suggest that it, or an allele in tight linkage disequilibrium (LD) with it, may contribute to as much as 35% of AD in the general population. Results support a model whereby decreased ACE activity may influence AD susceptibility by a mechanism involving β-amyloid metabolism.

Citation

Wilcock, G. K., Wilman, B., Kehoe, P. G., Katzov, H., Feuk, L., Bennett, A. M., …Prince, J. A. (2003). Haplotypes extending across ACE are associated with Alzheimer's disease. Human Molecular Genetics, 12(8), 859-867. https://doi.org/10.1093/hmg/ddg094

Journal Article Type Article
Publication Date Apr 15, 2003
Journal Human Molecular Genetics
Print ISSN 0964-6906
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 12
Issue 8
Pages 859-867
DOI https://doi.org/10.1093/hmg/ddg094
Keywords haplotypes, ACE, Alzheimer's
Public URL https://uwe-repository.worktribe.com/output/1073639
Publisher URL http://dx.doi.org/10.1093/hmg/ddg094




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